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E-health applications can support continuing care for persons with chronic diseases such as multiple sclerosis (MS). We have developed a web-based mobile app called VIOLA to be used at home by persons with MS (pwMS) who previously participated in an innovative multidisciplinary rehab program. The purpose of VIOLA is to reinforce what participants have learned about a healthy lifestyle and to keep them motivated to adhere to rehabilitation programs. As the outbreak of the Covid-19 pandemic has severely curtailed pwMS contact with their usual health providers, we quickly updated VIOLA to grant continuity of care to our home-bound patients.By monitoring pwMS subscriptions to individual modules, we found a definite increase after the national lockdown was declared. Subscribers rated the app very positively.Encouraged by the positive feedbacks, we are planning to extend the access to our app also to pwMS with no prior specific learning experience. This would limit the psychophysical consequences of the lockdown. Furthermore, VIOLA could be effective in maintaining a proper lifestyle, contributing to improve the quality of life of pwMS.VIOLA has the potential of increasing the adherence of pwMS to the rehabilitation confirming that digital communication tools are a valuable solution for those home-bound.].

Multiple sclerosis (MS) is a neurodegenerative inflammatory condition mediated by autoreactive immune processes. Due to its potential to influence host immunity and gut-brain communication, the gut microbiota has been suggested to be involved in the onset and progression of MS. To date, there is no definitive cure for MS, and rehabilitation programs are of the utmost importance, especially in the later stages. However, only a few people generally participate due to poor support, knowledge, and motivation, and no information is available on gut microbiota changes. Herein we evaluated the potential of a brief high-impact multidimensional rehabilitation program (B-HIPE) in a leisure environment to affect the gut microbiota, mitigate MS symptoms and improve quality of life. B-HIPE resulted in modulation of the MS-typical dysbiosis, with reduced levels of pathobionts and the replenishment of beneficial short-chain fatty acid producers. This partial recovery of a eubiotic profile could help counteract the inflammatory tone typically observed in MS, as supported by reduced circulating lipopolysaccharide levels and decreased populations of pro-inflammatory lymphocytes. Improved physical performance and fatigue relief were also found. Our findings pave the way for integrating clinical practice with holistic approaches to mitigate MS symptoms and improve patients’ quality of life.

Background Lombardy was the epicenter in Italy of the first wave of COVID-19 pandemic. To face the contagion growth, from March 8 to May 8 2020, a regional law re-designed the hub-and-spoke system for time-dependent diseases to better allocate resources for COVID-19 patients. Methods We report the reorganization of the major hospital in Lombardy during COVID-19 pandemic, including the rearrangement of its ICU beds to face COVID-19 pandemic and fulfill its role as extended hub for time-dependent diseases while preserving transplant activity. To highlight the impact of the emergently planned hub-and-spoke system, all patients admitted to a COVID-19-free ICU hub for trauma, neurosurgical emergencies and stroke during the two-month period were retrospectively collected and compared to 2019 cohort. Regional data on organ procurement was retrieved. Observed-to-expected (OE) in-ICU mortality ratios were computed to test the impact of the pandemic on patients affected by time-dependent diseases. Results Dynamic changes in ICU resource allocation occurred according to local COVID-19 epidemiology/trends of patients referred for time-dependent diseases. The absolute increase of admissions for trauma, neurosurgical emergencies and stroke was roughly two-fold. Patients referred to the hub were older and characterized by more severe conditions. An increase in crude mortality was observed, though OE ratios for in-ICU mortality were not statistically different when comparing 2020 vs. 2019. An increase in local organ procurement was observed, limiting the debacle of regional transplant activity. Conclusions We described the effects of a regional emergently planned hub-and-spoke system for time-dependent diseases settled in the epicenter of COVID-19 pandemic in Italy.

Introduction Juvenile idiopathic arthritis (JIA) is a chronic disease characterized by persistent joint inflammation. JIA is the most common pediatric chronic rheumatic disease and no curative therapy is currently available. Methotrexate (MTX) is an important treatment for JIA even though a high inter-individual variability in response is observed in patients. Among the factors of this variability, genetics and epigenetics might play an important role. Areas covered This review summarizes the results of pharmacogenetic and pharmacoepigenetic studies regarding MTX response in JIA. Studies considering epigenetic factors in JIA patients are still very limited, therefore this review includes also studies performed in adult patients with rheumatoid arthritis. Moreover, the relevance of biomarkers measured in blood or urine of JIA patients in relation to MTX treatment is discussed. Expert opinion Nowadays, even though many pharmacogenomics studies have been published, a specific genetic marker predictor of MTX efficacy or adverse events has not yet been identified. Encouraging results are available and great expectations rely on the study of epigenetics. Future studies are needed in order to identify genetic and epigenetic biomarkers that can be implemented in the clinical practice.

Background: Butyric acid (BA) is a short-chain fatty acid (SCFA) with anti-inflammatory properties, which promotes intestinal barrier function. Medium-chain fatty acids (MCFA), including caproic acid (CA), promote TH1 and TH17 differentiation, thus supporting inflammation. Aim: Since most SCFAs are absorbed in the cecum and colon, the measurement of BA in peripheral blood could provide information on the health status of the intestinal ecosystem. Additionally, given the different immunomodulatory properties of BA and CA the evaluation of their serum concentration, as well as their ratio could be as a simple and rapid biomarker of disease activity and/or treatment efficacy in MS. Methods: We evaluated serum BA and CA concentrations, immune parameters, intestinal barrier integrity and the gut microbiota composition in patients with multiple sclerosis (MS) comparing result to those obtained in healthy controls. Results: In MS, the concentration of BA was reduced and that of CA was increased. Concurrently, the microbiota was depleted of BA producers while it was enriched in mucin-degrading, pro-inflammatory components. The reduced serum concentration of BA seen in MS patients correlated with alterations of the barrier permeability, as evidenced by the higher plasma concentrations of lipopolysaccharide and intestinal fatty acid-binding protein, and inflammation. Specifically, CA was positively associated with CD4+/IFNγ+ T lymphocytes, and the BA/CA ratio correlated positively with CD4+/CD25high/Foxp3+ and negatively with CD4+/IFNγ+ T lymphocytes. Conclusion: The gut microbiota dysbiosis found in MS is possibly associated with alterations of the SCFA/MCFA ratio and of the intestinal barrier; this could explain the chronic inflammation that characterizes this disease. SCFA and MCFA quantification could be a simple biomarker to evaluate the efficacy of therapeutic and rehabilitation procedures in MS.

INTRODUCTION Inflammatory bowel disease is a chronic inflammation of the gut whose pathogenesis is still unclear. Although no curative therapy is currently available, a number of drugs are used in induction and maintenance therapy; however, for most of these drugs, a high inter-individual variability in response is observed. Among the factors of this variability, genetics plays an important role. Areas covered: This review summarizes the results of pharmacogenetic studies, considering the most important drugs used and in particular aminosalycilates, glucocorticoids, thiopurines, monoclonal antibodies and thalidomide. Most studies used a candidate gene approach, even if significant breakthroughs have been obtained recently from applying genome-wide studies. When available, also investigations considering epigenetics and pharmacogenetic dosing guidelines have been included. Expert opinion: Only for thiopurines, genetic markers identified as predictors of efficacy or adverse events have allowed the development of dosing guidelines. For the other drugs, encouraging results are available and great expectations rely on the study of epigenetics and integration with pharmacokinetic information, especially useful for biologics. However, to improve therapy of IBD patients with these drugs, for implementation in the clinics of pharmacogenetics, informatic clinical decision support systems and training about pharmacogenetics of health providers are needed.

BACKGROUND Grey Matter (GM) atrophy has been extensively described in Multiple Sclerosis (MS) patients, while cerebral hypoperfusion has been less consistently reported. Since hypoperfusion might be related to atrophy, we evaluated the presence of both damages. OBJECTIVE We aimed to assess if the regions of altered perfusion and atrophy overlapped with one another and if the two parameters were locally related. METHOD 3D-T1 weighted and arterial spin labelling sequences were acquired using a 1.5T Magnetic Resonance Imaging scanner from 26 relapsing remitting MS patients and 26 Healthy Controls (HC). GM volume and Cerebral Blood Flow (CBF) differences and their correlation were tested with a voxel-wise approach. RESULTS MS patients (41.4±12.5 years; 14 females) had a median [25th-75th percentile range] Expanded Disability Status Scale of 1.0[1.0-2.4] and a median [25th-75th percentile range] disease duration of 8.0 [4.0-16.5] years. HC were age- and sex-matched (43.9±17.4 years; 11 females). GM atrophy was detected for MS group in the right parahippocampal gyrus, thalami and left caudate (pFWE≤0.05). Areas of significant (after family-wise error -FWE- correction for multiple comparisons) (pFWE≤0.05) hypoperfusion were found for MS in the anterior cingulate and paracingulate gyri, supplementary motor cortex, precentral and superior frontal gyrus. GM volume and CBF showed a significant correlation (pFWE≤0.05) in the right lateral occipital cortex and precuneus in the MS group. CONCLUSIONS GM atrophy and hypoperfusion in MS were located in different areas. Perfusion estimate might be used as a further marker of tissue damage, in addition to GM volume.

Background Intestinal inflammation and epithelial injury are the leading actors of inflammatory bowel disease (IBD), causing an excessive pro-inflammatory cytokines expression. Tristetraprolin (TTP), an mRNA binding protein, plays a role in regulating the inflammatory factors, recognizing specific sequences on the 3' untranslated region of cytokine mRNAs. TTP activity depends on its phosphorylation state: the unphosphorylated TTP degrades pro-inflammatory cytokine mRNAs; on the contrary, the phosphorylated TTP fails to destabilize mRNAs furthering their expression. The phospho-TTP forms a complex with the chaperone protein 14-3-3. This binding could be one of the factors that promote intestinal inflammation as a cause of disease progression. Aim To assess if TTP phosphorylation has a role in paediatric IBD. Methods The study was carried out on a cohort of paediatric IBD patients. For each patient enrolled, a specimen of inflamed and non-inflamed colonic mucosa was collected. Furthermore, the experiments were conducted on macrophages differentiated from blood samples of the same patients. Macrophages from healthy donors' blood were used as controls. Co-immunoprecipitation assay and immunoblotting analyses were performed to observe the formation of the phospho-TTP/14-3-3 complex. In the same samples TNF-α expression was also evaluated as major factor of the pro-inflammatory activity. Results In this work we studied indirectly the phosphorylation of TTP through the binding with the chaperone protein 14-3-3. In inflamed and non-inflamed colon mucosa of IBD paediatric patients immunoblot assay demonstrated a higher expression of the TTP in inflamed samples respect to the non-inflamed; the co-immunoprecipitated 14-3-3 protein showed the same trend of expression. In the TNF-α gene expression analysis higher levels of the cytokine in inflamed tissues compared to controls were evident. The same experiments were conducted on macrophages from IBD paediatric patients and healthy controls. The immunoblot results demonstrated a high expression of both TTP and co-immunoprecipitated 14-4-3 protein in IBD-derived macrophages in comparison to healthy donors. TNF-α protein levels from macrophages lysates showed the same trend of expression in favour of IBD paediatric patients compared to healthy controls. Conclusion In this work, for the first time, we describe a relation between phospho-TTP/14-3-3 complex and IBD. Indeed, a higher expression of TTP/14-3-3 was recorded in IBD samples in comparison to controls.

Background: The long non-coding RNA (lncRNA) growth arrest&ndash, specific transcript 5 (GAS5) seems to be involved in the regulation of mediators of tissue injury, in particular matrix metalloproteinases (MMPs), implicated in the pathogenesis of inflammatory bowel disease (IBD). We investigated the role of GAS5 in regulating MMP2 and MMP9 expression in pediatric patients with IBD and in vitro. Methods: In total, 25 IBD patients were enrolled: For each patient paired inflamed and non-inflamed biopsies were collected. RNA was extracted and GAS5, MMP2, and MMP9 were quantified by TaqMan assay. The expression of GAS5 and MMPs was also determined in the human monocytic THP1 cells differentiated into macrophages and stimulated with lipopolysaccharide (LPS). The function of GAS5 was assessed by overexpressing the lncRNA and evaluating the MMPs levels. Results: Real-time PCR results demonstrated a downregulation of GAS5 and an upregulation of both MMPs in inflamed tissues. In vitro data confirmed the trend observed in patients for the three genes: The stimulation with LPS promoted a downregulation of GAS5 while an increase of MMPs was observed. Overexpression experiments showed that higher levels of GAS5 lead to a decrease of both enzymes. Conclusion: These results provide new information about the role of GAS5 in IBD: The lncRNA could mediate tissue damage by modulating the expression of MMPs.

Background: The management of people affected by age-related neurological disorders requires the adoption of targeted and cost-effective interventions to cope with chronicity. Therapy adaptation and rehabilitation represent major targets requiring long-term follow-up of neurodegeneration or, conversely, the promotion of neuroplasticity mechanisms. However, affordable and reliable neurophysiological correlates of cerebral activity to be used throughout treatment stages are often lacking. The aim of this systematic review is to highlight actual applications of functional Near-Infrared Spectroscopy (fNIRS) as a versatile optical neuroimaging technology for investigating cortical hemodynamic activity in the most common chronic neurological conditions. Methods: We reviewed studies investigating fNIRS applications in Parkinson’s Disease (PD), Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI) as those focusing on motor and cognitive impairment in ageing and Multiple Sclerosis (MS) as the most common chronic neurological disease in young adults. The literature search was conducted on NCBI PubMed and Web of Science databases by PRISMA guidelines. Results: We identified a total of 63 peer-reviewed articles. The AD spectrum is the most investigated pathology with 40 articles ranging from the traditional monitoring of tissue oxygenation to the analysis of functional resting-state conditions or cognitive functions by means of memory and verbal fluency tasks. Conversely, applications in PD (12 articles) and MS (11 articles) are mainly focused on the characterization of motor functions and their association with dual-task conditions. The most investigated cortical area is the prefrontal cortex, since reported to play an important role in age-related compensatory mechanism and neurofunctional changes associated to these chronic neurological conditions. Interestingly, only 9 articles applied a longitudinal approach. Conclusion: The results indicate that fNIRS is mainly employed for the cross-sectional characterization of the clinical phenotypes of these pathologies, whereas data on its utility for longitudinal monitoring as surrogate biomarkers of disease progression and rehabilitation effects are promising but still lacking.

Background: Multiple sclerosis (MS) has a relevant impact on quality of life (QOL) and is associated with increased risks of psychological morbidity. Mindfulness-based interventions (MBIs) are among the most studied interventions, although few well-conducted studies have tested them in this field. Furthermore, the participation in typical MBIs may be impaired by time and logistics. Objective: We aimed to test the efficacy of an online MBI to improve QOL, psychological well-being, sleep, and fatigue. Methods: We conducted a randomized controlled trial, in which 139 participants were randomly assigned to an MS-specific online mindfulness meditation intervention or to a psychoeducational (active control) group. Participants were assessed for QOL, depression, anxiety, sleep problems, and fatigue, at three different times: at recruitment, after 2 months, and after 6 months. Results: In comparison to the control group, the experimental subjects reported higher QOL and lower depression, anxiety, and sleep problems at the end of intervention. However, after 6 months these group differences were no longer significant. Conclusion: An online MBI could be an effective psychological treatment for the promotion of well-being in MS in short-term. However, the lack of lasting effects requires the development of new strategies to support long-term changes.

Background Thalidomide is an effective drug in children with inflammatory bowel disease (IBD) refractory to standard treatments, however, its use is often limited by its safety profile, in particular for the risk of teratogenicity and peripheral neuropathy. Multiple hypotheses exist to explain the molecular mechanism of thalidomide action but no data have been published on IBD patients. To identify determinants of thalidomide action in paediatric IBD, high-throughput microRNA (miRNA) and messenger RNAs (mRNA) profiles during treatment were analysed. Methods IBD patients responsive to thalidomide were enrolled. miRNA and mRNA profiles from peripheral blood obtained before and after 12 weeks of treatment were determined using next-generation sequencing. Differentially expressed genes were identified by fold change from the general linear model. In order to detect the potentially altered pathways, the hypergeometric test based on gene ontology annotations was used. The identification of putative mRNA targets of thalidomide sensitive miRNAs was performed by Targetscan database. Results Ten IBD paediatric patients (mean age 13.1 years, 6 males) were enrolled. Sequencing analysis identified 10 miRNAs (3 downregulated) and 252 mRNAs (76 downregulated) deregulated after treatment. Five upregulated miRNAs could putatively recognise the 3′UTR of several Hox genes, a group of transcription factors that play important roles in the development of structures such as limbs, lungs and nervous system. The hypergeometric test highlighted the altered pathways involved in inflammatory response, regulation of immune system, prostaglandin receptor activity and G protein-coupled receptor signalling. Among the 10 miRNAs deregulated by thalidomide, six could putatively regulate the differentially expressed mRNAs resulting from the analyses. Conclusion Thalidomide induces specific gene expression alterations, which could help to elucidate its molecular mechanism in paediatric IBD patients. miRNA results may suggest new molecular targets involved in the teratogenic effects of this drug. Moreover, mRNA profiles indicate a strong involvement of adenylate cyclase-modulating G protein-coupled receptor signalling in the thalidomide mechanism of action.

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We assessed cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) within gray matter (GM), normal appearing white matter (NAWM) and white matter (WM) lesions in a group of multiple sclerosis (MS) patients. Furthermore, correlations between CBF, CVR and age were investigated. 31 MS patients and 25 healthy controls (HC) were examined on a 1.5 T MRI scanner, using pseudo-continuous arterial spin labeling MRI. MS vs HC CBF and CVR differences were assessed in GM regions of interest (i.e. resting state networks and vascular territories), and within WM. Correlations between CBF/CVR and age were then computed for MS and HC groups. Whereas no significant CBF and CVR differences were observed between MS and HC in any of the considered brain areas, significantly lower CBF was found in WM lesions with respect to NAWM (p

Objective: Only a limited percentage of persons with MS (pwMS) participate to multidisciplinary rehabilitation (MDR) because of poor support, knowledge and motivation. We reasoned that pwMS should be more effectively prepared to increase their adherence. We implemented an innovative collaborative approach, called “brief highimpact preparatory experience” (b-HIPE), inspired by an overarching model based on the interplay between competence, motivation and opportunity to increase in a short time awareness and motivation of pwMS. Methods: B-HIPE integrates physiotherapy, mindfulness, sailing, healthy diet, and cultural activities to be experienced in a convivial form at a beautiful seaside location in Sardinia. Sixteen pwMS participated to 3 successive one-week editions of the b-HIPE, co-sponsored by the Rotary Club of Milan and supported by researchers of our Institute and of partner associations. The feasibility was assessed with structured questionnaires and free reports concerning accommodation, logistics, coordination, social climate and the specific activities proposed. For this pilot study we used a single-group design with repeated measurements at baseline and post-intervention. The SF-36 QoL scale was the main outcome measure, the Fatigue Severity Scale (FSS), the Berg Balance scale (BBS) and the 9 hole peg test (9HPT) were the secondary outcomes. Results: The approach was feasible. Scores on several FS-36 scales and secondary outcomes were significantly improved. Participants’ satisfaction with all aspects of the experience was above expectations. PwMS became more motivated and aware of physical and mental resources, all learned to sail adapted monohulls, strategies to master stress and to modify their diet according to specific recommendations. Conclusion: B-HIPE is safe and feasible. The interplay of multiple factors produced in a very short time the expected changes in participants’ attitude toward a healthier lifestyle. A monitoring program is ongoing to assess long-term effects including adherence to hospital-based MDR. Publisher PDF

Iatrogenic vascular injury during lumbar disk surgery, although rare, is a serious complication, and when it does occur, can be sudden and life-threatening. The risk of injury to the pelvic vessels intra-operatively can be explained by the close proximity of the retroperitoneal vessels to the vertebral column therefore causing injury to the anterior longitudinal ligament, which can give access to the retroperitoneal space. If signs of circulatory instability are noted during lumbar disk surgery, early diagnosis of vascular injury and urgent transperitoneal surgery or emergency stenting can save the patient's life. Here, is presented the case of a 52-year-old man who underwent an elective lumbar discectomy for a rightward disk herniation in the L4–L5 intervertebral space and died 12 h after the operation for a hemorrhagic shock due to a severe intra-abdominal hemorrhage following iatrogenic left common iliac artery and vein perforation during lumbar discectomy.

Long-term ecological research (LTER) is performed in many countries across the globe by scientists that gather and analyse multidecadal ecological observations and data, to support understanding and management of the environment. LTER data are used to describe the state and dynamics of an ecosystem. This valuable research is in charge of experts in ecology, and it is performed in the so-called LTER networks (for Europe, see http://www.lter-europe.net), usually organized at a national level; they consist of sites covering different ecosystem typologies, each one with research and monitoring facilities. In summer 2015, researchers of the Italian LTER network (LTER-Italy) have created a set of naturalistic trails, connecting sites of LTER-Italy (http://www.lteritalia.it/cammini), aiming to transfer and share the research results with citizens, through public events and informal science communication. Along one of these trails, performed on the Alps, the organizers proposed the use of two VGI apps to collect either biological or abiotic observations (http://www.lteritalia.it/it/content/citizenscience). The apps were chosen according to crucial characteristics, i.e. offline usage, operative system independence, strong development and support community, customization of user interfaces. This paper reports on this first test, discussing lessons learned and, in particular, the impact on the practice of research communities of participative, innovative tools, often neglected in the analysis of mobile application effects.

The concurrent usage of actigraphy and heart rate variability (HRV) for sleep efficiency quantification is still matter of investigation. This study compared chest (CACT) and wrist (WACT) actigraphy (actigraphs positioned on chest and wrist, respectively) in combination with HRV for automatic sleep vs wake classification. Accelerometer and ECG signals were collected during polysomnographic studies (PSGs) including 18 individuals (25-53 years old) with no previous history of sleep disorders. Then, an experienced neurologist performed sleep staging on PSG data. Eleven features from HRV and accelerometry were extracted from series of different lengths. A support vector machine (SVM) was used to automatically distinguish sleep and wake. We found 7 min as the optimal signal length for classification, while maximizing specificity (wake detection). CACT and WACT provided similar accuracies (78% chest vs 77% wrist), larger than what yielded by HRV alone (66%). The addition of HRV to CACT reduced slightly the accuracy, while improving specificity (from 33% to 51%, p 0.05). On the contrary, the concurrent usage of HRV and WACT did not provide statistically significant improvements over WACT. Then, a subset of features (3 from HRV + 1 from actigraphy) was selected by reducing redundancy using a strategy based on Spearman's correlation and area under the ROC curve. The usage of the reduced set of features and SVM classifier gave only slightly reduced classification performances, which did not differ from the full sets of features. The study opens interesting possibilities in the design of wearable devices for long-term monitoring of sleep at home.

The case here reported involves a schizophrenic 19-year-old girl under treatment with clotiapine, which was well tolerated except for a moderate dry mouth. The woman ingested a whole sole (Solea solea), which caused a very rapid death by choking. A complete autopsy was performed 24 h later, as well as histological and toxicological analysis. At autopsy, the sole was wedged in the esophagus causing a choking ab extrinseco. The fish had a length of 18 cm and a maximum width of 6 cm, weighing 188.7 g. Toxicological analysis detected 0.57 mg/L of clotiapine in blood, which falls within the therapeutic range. The peculiarity of this case is represented by two factors: one is the choking by fish and the second was the adverse affect caused by clotiapine, which induced a condition of dry mouth making the act of swallowing even more difficult, thereby contributing to a very rapid mechanical asphyxia and the death of the young woman.

The aim of this retrospective study was to preliminarily assess whether the EP-score, a summary score derived from multimodal evoked potentials tests, might be used as a measure of treatment efficacy in multiple sclerosis (MS).A sample of 56 relapsing remitting MS (RRMS) patients who at diagnosis started treatment with interferon β (INFβ, n = 19), glatiramer acetate (GA, n = 15) or refused any chronic treatment were assessed at baseline (before treatment) and at a median of 1.7 and 3.6 years thereafter. Outcome variables were Expanded Disability Status Scale (EDSS), EP-Score, visual evoked potentials (VEP) and somatosensory evoked potentials (SEP) scores measured as differences between baseline and follow-ups. Statistical differences between groups and follow-ups were assessed using non-parametric analyses.Treatment effects were not significant for EDSS both at the first and at the second follow-up, while a trend toward significance was observed in the EP-score only in the first follow-up (p = 0.07). Post-hoc analysis showed a greater decrease in median VEP-score for the IFNβ group compared to the GA and DF groups at both the first and second follow-ups.We found no evidence that either INFβ or GA significantly improved disability in RRMS patients. Using the EP-score as an outcome measure, we found that it was improved at both follow-ups in the INFβ group mainly due to a decrease in the VEP-score. This finding supports the proposal to include the EP-score as an additional outcome variable in future studies of treatment efficacy in MS.

The usefulness of sympathetic skin responses (SSR) in multiple sclerosis (MS) has been advocated by several studies in the last 20 years; however, due to a great heterogeneity of findings, a comprehensive meta-analysis of case-control studies is in order to pinpoint consistencies and investigate the causes of discrepancies. We searched MEDLINE, EMBASE and Cochrane databases for case-control studies comparing SSR absence frequency and latency between patients with MS and healthy controls. Thirteen eligible studies including 415 MS patients and 331 healthy controls were identified. The pooled analysis showed that SSR can be always obtained in healthy controls while 34% of patients had absent SSRs in at least one limb (95% CI 22–47%; p

The color-word Stroop paradigm is a neuropsychological test often employed for the evaluation of the cognitive processing when a conflict between different attributes of the same visual stimulus is present. In clinical environments, the standard practice for the Stroop test administration is still based on paper supports and stopwatches. Thus, the aim of the present pilot study was to investigate the usability in clinical practice of a completely computerized system for the Stroop test administration. The computerized system developed for this study was made up of the following modules: i) a PC for stimuli administration and data acquisition connected to two monitors (one for the user, the other for the experimenter); ii) a response system composed of three colored electronic buttons; iii) a wireless electroencephalography (EEG) acquisition module (i.e. headset and dedicated software). The system was installed in the IRCCS Don Carlo Gnocchi Foundation and tested on 7 subjects hospitalized in the neurorehabilitation Unit. The developed system was able to provide information about the subjects' reaction time to stimuli in addition to the traditional behavioral scores. Moreover, the integrated EEG acquisition module allowed monitoring the user's engagement during the test through the computation of a simple EEG-based evaluation index. We believe that this pilot study could set a further step towards the clinical use of computerized systems to monitor cognitive functions.

Ménière disease (MD) is a chronic illness of the inner ear that affects a substantial number of patients every year worldwide. Because of a dearth of well-controlled studies, the medical and surgical management of MD remains quite empirical. The main reason is that it is very difficult to investigate patients affected with Certain MD due to the post-mortem criterion necessary for this diagnostic grade. Although Endolymphatic Hydrops (EH) is the worldwide accepted mechanism of MD, the causes that induce it are still not clear. In fact MD has been correlated mostly to a wide and different disturbances ranging from trauma to sleep disorders. It is nowadays sufficiently demonstrated that Chronic Cerebro Spinal Venous Insufficiency (CCSVI) is very frequent in MD. Even if CCSVI may potentially induce EH through a pure hydraulic mechanism CCSVI, per se does not explain how the various disorders correlated with MD may interact with CCSVI and provoke EH. The aim of this review is an attempt to approach MD into the context of the more recent findings about the global brain waste clearance system, to which inner ear is anatomically and functionally connected, in order to build a reasonable model of MD pathogenesis. The major part of the diseases correlated to MD may act on the inner ear disturbing the Glymphatic (GS) and/or Brain Lymphatic System (BLS) activity. The venous system interplays with GS and BLS. In this model CCSVI is considered more than a direct cause of MD rather the anatomical predisposition to develop the disease. In this model EH, and then MD, is the consequence of a failure of the compensation of the congenital venous abnormalities, anatomical compensation as collateral pathways and/or functional compensation as GS and BLS. In this model the major part of the disturbances correlated to MD and the various treatment proposed find their appropriate placement.

Background Mindfulness-based interventions, modified and shortened versions of meditation teachings, have proved to be effective in the improvement of quality of life in many clinical conditions, including chronic diseases. Preliminary results available in the literature and in clinical experience indicate a high potential for this treatment for the reduction of psychological suffering in people with chronic diseases. Methods/Design This randomized controlled trial will investigate the impact of a multiple sclerosis (MS) specific telemedicine meditation intervention on the quality of life of people with multiple sclerosis and their caregivers. This trial will recruit 120 patients, men and women, with a diagnosis of relapsing-remitting or secondary progressive MS and their caregivers to participate in a 2-month intervention. Patients will undergo assessments of quality of life, anxiety, depression, quality of sleep, mindfulness and fatigue levels conducted at baseline, at week 8 (conclusion of the intervention) and at week 27 (6 months follow-up). Caregivers will complete assessments conducted at the same time for the same areas, plus caregiver burden. The intervention condition will consist of 2 hours/week of online meditation in a group setting led by a trainer, plus 1 hour/week of individual exercises. The control condition will incorporate a psycho-education online program and will require the same contact time commitment as the intervention condition. Discussion Primary outcome measures will consist of assessments of quality of life, anxiety, and depression level. Assessments of mindfulness level, quality of sleep and fatigue level will be considered secondary outcome measures. This investigation will increase understanding of the role of meditation as part of a treatment plan for people with MS and their caregivers. Overall, this study design has the potential to lead to effective meditation intervention strategies for this population and improve their quality of life. Trial registration Clinical Trials Register NCT02364505. https://clinicaltrials.gov/ct2/show/NCT02364505

Patients with multiple sclerosis (MS) frequently report symptoms related to vestibular disorders in the course of their disease. At present, the fundamental tests assessing vestibulospinal involvement are posturography and vestibular evoked myogenic potentials (VEMPs). While posturography cannot be performed in every subject requiring minimal stance control, VEMPs do not require any specific skill on the part of the subjects and they may be investigated in all patients able to sit. VEMPs were recorded for 40 patients (17 men, 23 women; mean age 38 years, range 17-71 years) fulfilling diagnostic criteria of clinically defined MS, by means of rarefaction clicks, recording modulation of sterno-cleido-mastoideus tonic contraction saccule-mediated modulation. VEMPs were found to be abnormal in 28 of 40 patients. In 18 of the cases the VEMPs were asymmetric, i.e., had a prolonged latency on one side. In six cases latency was increased on both sides (mean delay 4.1 ms). In four subjects VEMPs were absent on one side. C oncordance with clinical findings of presence/absence of brainstem involvement was found in 55% and with MRI findings in 65% of the cases. A bnormal VEMPs indicated brainstem dysfunction in four patients (10%) with normal MRI and no specific clinical signs.

Paroxysmal positioning vertigo (PPV) is a major cause of vertigo accounting for 14 % of all equilibrium disorders with an annual incidence of about 100 per 100,000 of population [1]. It starts suddenly and is usually first noticed in bed, when waking from sleep. Any turn of the head seems to bring on violent but brief bursts of dizziness. Patients often describe the occurrence of vertigo with tilting of the head, looking up or down, or rolling over in bed. It is not unusual for nausea and vomiting to accompany the vertigo. Even if a spell is brief, a feeling of queasiness may last several minutes or even hours, and those who suffer from this kind of vertigo are distressed and incapacitated for several days severely impacting on social costs due to lost working days. PPV is a common vestibular disorder leading to significant morbidity, psychosocial impact, and medical costs. PPV accounted for 8 % of individuals with moderate or severe dizziness/vertigo. Is commonly accepted that PPV is due to displacement of otoconia and/or to vestibular macula/maculae lesion.

The recording and measurement of central and peripheral nervous system responses can provide important information during the development and the application of virtual reality (VR). Although studies on electroencephalographic, evoked potentials, and peripheral psychophysiological changes in connection with VR exposure are still preliminary, they show that reliable data can be obtained even in immersive VR conditions. There is no firm evidence that neurophysiological equipment—sensors and cables—may increase subjects' discomfort and affect their ability to interact with the virtual environments, but additional study is needed to clarify this issue. Suggestions as to how to limit potential interferences are summarized here. Two main lines of research are emerging: one seeking psychophysiological correlates of reaction and adaptation to stimuli and task variables in an attempt to understand more about human-VR interaction, and the other looking for ways to use psychophysiological responses to automatically control aspects of the virtual environments or other external devices. The main results emerging from the first group of studies indicate that psychophysiological measures of brain activity—notably EEG and event-related responses—may be used to distingush between automatic and controlled modes of processing. Additionally, peripheral measures, notably skin-resistance levels, are proposed as objective correlates of presence and of the outcome of specific VR-based desensitization therapies. There is no clear-cut evidence that brain waves may index unwanted effects on the central nervous system of VR exposure, but this issue deserves further study. The results of the second line of research seem to indicate that VR-induced psychophysiological responses can be used to develop assistive devices for people with disabilities or to control hands-free interaction within any virtual environment (for example, in highly demanding conditions). A related and promising field of application is that of neurofeedback, wherein VR may play an important role in increasing the motivational/ attentional span of clients, and, ultimately, the effectiveness of treatment protocols. Given these premises, it is suggested that research on psychophysiological correlates of VR should be incremented along the lines already delineated and possibly include also groups of subjects at risk for adverse affects.

Traumatic aneurysms or dissections of the vertebral artery have been reported in patients who have suffered minor craniofacial injuries in traffic accidents. A case is reported of ruptured traumatic vertebral artery aneurysm due to closed head injury without without penetrating injuries or skull fractures. The macroscopic and histological findings relevant to the vertebral wall were compatible with post-traumatic aneurysm; the rupture of the wall was assumed to be caused by sepsis and local infiltration of inflammatory cells.

Corticobasal degeneration (CBD) presents with symptoms that often overlap with other neurological conditions. In many cases, diagnosis, prognosis and consequent clinical management remain uncertain. Structural and functional asymmetric brain changes represent the most consistent imaging findings that may assist in CBD diagnosis. Diffusion Tensor MRI (DT-MRI) is a quantitative technique that allows microscopic tissue abnormalities to be non-invasively assessed in vivo. A single case of clinically suspected CBD with symmetric diffuse brain atrophy on conventional-MRI scans was studied using DT-MRI by voxel-wise comparison with eight healthy subjects. The lateralized distribution of DT-MRI abnormalities was consistent with clinical features providing a substantial support to the diagnosis. (C) 2008 Elsevier Ltd. All rights reserved.

A group of worldwide virtual reality and health-care researchers have decided to combine their efforts in a multidisciplinary project titled VETERAN – virtual environments in the diagnosis, prevention and intervention of age-related diseases. The main goal of the VETERAN project is the tuning and testing of different virtual environments, designed to address the cognitive/functional impairments that may occur due to the aging process and age-related disorders. In particular the developed modules will address the problems commonly found in the following pathologies that have a strong impact on the elderly health care policy: Alzheimer’s disease and other senile dementias; stroke and unilateral spatial neglect; mobility-related accidents within specific environments (e.g., falls, shocks). The project will focus on research into clinical aspects of age-related diseases and disorders of high morbidity and specifically target goals of prevention, treatment, or delay in onset. Another goal of the VETERAN project is to define and develop new protocols and tools to be used for general rehabilitation purposes. These tools will aim to provide systematic restorative training within the context of functionally relevant, ecologically valid simulated environments This approach is hoped to optimize the degree of transfer of training and/or generalization of learning to the person’s real world environment. (Less)

This study investigated whether exploration of computer-generated environments can selectively enhance spatial memory in patients with multiple sclerosis (MS). Fifteen patients and 15 healthy subjects who controlled their movements in a virtual house using a joystick recalled the spatial layout of the environments better than 15 patients and 15 controls who merely watched the active participants' progress. Among passive subjects, only healthy controls did significantly better than active participants in the recall of virtual objects. There were no significant differences between active and passive participants' recall of correct object locations in the virtual environments. MS patients' recall of the spatial layout and of the virtual objects was significantly worse than that of healthy subjects, but patients' data did not correlate with traditional neuropsychological measures of spatial memory. It is suggested that virtual reality can be used in MS patients to assess aspects of spatial memory that are not measured by traditional tests.

To devise a multivariate parametric model for short-term prediction of disability using the Expanded Disability Status Scale (EDSS) and multimodal sensory EP (mEP). A total of 221 multiple sclerosis (MS) patients who underwent repeated mEP and EDSS assessments at variable time intervals over a 20-year period were retrospectively analyzed. Published criteria were used to compute a cumulative score (mEPS) of abnormalities for each of 908 individual tests. Data of a statistically balanced sample of 58 patients were fed to a parametrical regression analysis using time-lagged EDSS and mEPS along with other clinical variables to estimate future EDSS scores at 1 year. Whole sample cross-sectional mEPS were moderately correlated with EDSS, whereas longitudinal mEPS were not. Using the regression model, lagged mEPS and lagged EDSS along with clinical variables provided better future EDSS estimates. The R 2 measure of fit was significant and 72% of EDSS estimates showed an error value of ±0.5. A parametrical regression model combining EDSS and mEPS accurately predicts short-term disability in MS patients and could be used to optimize decisions concerning treatment.

We investigated frontal cognitive function in a group of 153 patients with multiple sclerosis and 100 healthy controls using a global scale composed by a set of items from the Luria-Nebraska Neuropsychological Battery (LNNB) which has been validated by Malloy and colleagues on frontally damaged patients. A second scale was built with LNNB items tapping parietal lobes function. Patients who were specifically impaired on the frontal scale (12%) had a shorter disease duration and were less physically disabled than those failing on the parietal tasks (8.5%) or those showing combined deficits (21.5%). Sixty-four patients were also tested on the Wisconsin Card Sorting Test (WCST). Twenty-seven (37.5%) patients were found to be impaired on the WCST, but the latter could not predict reliably their performance on the LNNB frontal scale. We also examined whether age of onset and disease duration could have had any effect on the cognitive performance of selected groups of patients. We found that relative to normals, deficits on the frontal scale were more severe in patients with a clinical onset around age 20 than in patients with a later onset (i.e., around 35), the two groups being comparable for duration and degree of disability. Furthermore, patients with a longstanding illness (> 10 years) were more affected on visuospatial processing and frontal control of language than those with a short duration (1.5 yrs). We propose that a greater disease activity interacting with contingent (developmental?) factors is responsible for the appearance of transient frontal deficits in several young MS patients. A differential involvement of long associative and connecting bundles is also proposed as a basis for understanding the pattern of cognitive deficits encountered in selected patient groups.

Electroencephalogram (EEG) reactivity to eyes opening and 12-Hz photic stimulation was investigated in 14 healthy elderly subjects, 21 parkinsonian patients (PD), 7 demented parkinsonian patients (PDD), and 10 patients with Lewy body dementia (LBD) using global field synchronization (GFS). During eyes closed Theta GFS was increased in Parkinson's disease and patients and alpha1 GFS was decreased in LBD subjects. During 12-Hz intermittent photic stimulation (IPS), reactivity of posterior electrodes was decreased in PD and LBD patients. No reactivity was observed in PDD. Results are consistent with a graded posterior cortical disconnection in parkinsonian syndromes and with a model of dopamine-modulated thalamocortical interplay in visual processing.

Background: poor sleep is common in MS and it contributes to fatigue. The β interferons produce systemic effects which may not adapt and may induce fatigue. Objective: to verify whether subjective poor sleep and fatigue during chronic therapy correspond to reduced sleep efficiency obtained by actigraphy at home. Methods: 42 ambulatory relapsing remitting MS patients with mild disability were monitored for at least 7 nights. Habitual sleep quality and fatigue were assessed with the MOS sleep measure and the Fatigue Severity Scale. Sleep logs provided daily sleep quality assessments during actigraphy at home. Patients were grouped according to their current treatment: no therapy, glatiramer acetate, IFNβ 3 times a week, and IFNβ once a week. Results and Conclusion: sleep efficiency was reduced by an average of 5% in 2/3 of the nights following IFNβ injections compared to the other nights, and daily sleep ratings correlated with actigraphy. Patients on glatiramer acetate also showed a lower sleep efficiency than patients without therapy. Actigraphy data were only modestly correlated with MOSsm scores, not with fatigue. Long term adaptation of sleep effects of immunomodulant agents is incomplete and needs to be considered in treatment planning and assessment of sleep in MS.

Previous studies evaluated the self-affine characteristics of the electroencephalogram (EEG) by Detrended Fluctuations Analysis (DFA). This has been done by computing scaling exponents α over certain time-scales. However, literature is not univocal regarding i) the number of α coefficients which properly describe the EEG self-affinity, and ii) the temporal regions over which the coefficients should be estimated.

The prokaryotic community, both in terms of abundance and activity (exo-enzymatic hydrolysis of proteins, polysaccharides and phosphorylated molecules and leucine uptake), was investigated seasonally for a 3-year period (2004-2006) in the Gulf of Venice (northern Adriatic Sea). By focusing on spatial and temporal variability, the prokaryote dynamics showed significant variations on a horizontal and seasonal scale, but no substantial differences were observed among years. The basin-scale variability was mainly influenced by allochthonous inputs from the Po river and the Venice Lagoon, which were the main source of nutrients, acting as a 'bottom up' control on prokaryotes. On a seasonal scale, all the microbial parameters (except the polysaccharide degradation) showed significant variations following the temperature fluctuations. The annual rate of change was very low for all the chemical, physical and biological parameters and only the abundance and phosphatase activity of the prokaryotes differed significantly among years.

Peripheral blood lymphocyte subsets and serum immunoglobulin levels were assessed in 42 patients and 37 healthy controls. 24 patients were free from neuroleptic medication and 15 had never been treated with neuroleptics. 31 patients had a diagnosis of schizophrenia (DSM-III criteria) and 11 a diagnosis of a disorder of the schizophrenic spectrum. As compared to healthy subjects, the drug naive schizophrenic patient group showed an increase of T suppressor lymphocytes, while the drug-treated schizophrenic group showed an increase of T helper lymphocytes. The drug-treated schizophrenic group differed from the drug naive one relative to a decrease of T suppressor lymphocytes. As compared to healthy subjects, the drug naive spectrum disorder patients showed an increase of absolute number of lymphocytes, while the drug treated spectrum group showed an increase of B lymphocytes. These findings did not correlate with any clinical or neuromorphological variables taken into account.

The size distribution of the phytoplankton community has been analyzed on a monthly basis in the Gulf of Venice (NW Adriatic Sea), with the aim to assess the seasonal variation of the contribution of autotrophic picoplankton (APP) to total phytoplankton. The investigation was carried out in two stations characterized by different influences of fluvial inputs. APP was mainly made up of Synechococcus, the larger fraction (Utermohl Fraction Phytoplankton, UFP: >2 µm as maximum linear dimension) of diatoms and nanoflagellates. The average APP abundance (46 × 10 3 cells ml ‐1 ) and biomass (8.1 µg C dm ‐3 ) indicate that APP was a persistent and significant component of the NW Adriatic phytoplankton. The highest APP abundance (up to 270 × 10 3 cells ml ‐1 ) and biomass (up to 49 µg C dm ‐3 ) were recorded from summer to autumn, UFP peaked from late winter to late spring. The mean APP contribution to total phytoplankton abundance and biomass was 98% and 31% respectively. The seasonal variation of total phytoplankton biomass was mainly driven by the UFP fraction; however, a seasonal shift in the relative importance of UFP and APP occurred from spring to summer.

Equilibrium disorders caused by involvement of brainstem and cerebellar structures are common in patients with multiple sclerosis (MS), but peripheral conditions such as benign paroxysmal positional vertigo (BPPV) can be sometimes confused with those of a central origin. Therefore, an accurate otoneurologic investigation paying attention to differential diagnosis aspects should be performed in these subjects. Among available diagnostic tools, electro-oculography, posturography and vestibular evoked myogenic potentials (VEMPs) are especially suited to assess vestibulo-oculomotor and vestibulospinal systems. This paper briefly describes the most recent otoneurologic diagnostic strategies for MS patients and the results of initial clinical experiences, and finally provides suggestions for differentiating MS-related vestibular disorders from other common otoneurological conditions.

This study aimed to assess the efficacy and specificity of direct computer-assisted memory retraining (CR) in MS patients, in comparison to non-specific retraining, while controlling for severity of impairment, psychiatric symptoms and retest effects. Sixty patients with definite MS and a stable clinical condition were selected. All were assessed neuropsychologically and divided into three matched groups. One group received an 8-week specific CR programme (SCRP) and another received a non-specific 8-week CR programme (NCRP) to retrain attention; a third (control) group received no treatment. After the programmes were completed, all patients were reexamined with the same test battery. Patients were impaired on all 11 memory and attention tests at baseline. Those who received SCRP improved on 7 memory outcome measures, compared to only 1 in the NCRP group and none in the control group. Attention training had no significant effect on relevant outcome measures. Some non-retrained patients showed deterioration of cognitive performance at retest. These results indicate that direct memory training in MS patients is effective in the short-term and is specific. In selected cases, benefits extended to everyday life activities.

We studied the relationships between magnetic resonance imaging (MRI) and the Luria-Nebraska Neuropsychological Battery (LNNB) in 64 patients with relapsing-remitting multiple sclerosis (MS). MRI films were scored according to arbitrary descriptive criteria designed to emphasize patterns of alterations. Five groups were created: group 1 and 2 had typical discrete white matter lesions, group 3 had confluent lesions, group 4 had large discrete lesions and group 5 had only few small lesions. In addition, groups 2 and 3 had evidence of parenchymal atrophy. Groups 2 and 3 were the most impaired on the LNNB, but none of these patients was actually demented. Groups 1 and 5 were globally intact in spite of very different mean age and MRI pattern. Group 4 was composed of younger subjects with a shorter disease duration; they showed mild loss of attentive and abstracting abilities. We suggest that since their MRI was showing greater signs of local biological activity their mental deficits may be a transitory condition capable of two distinct outcomes: a favorable one as in groups 1 and 5, and a slowly progressive one associated with loss of brain tissue as in groups 2 and 3.

A clinical study has been conducted on a selected group of 9 children and 12 adults with attention deficit disorder, evaluating the response to the therapy with magnesium pemoline by means of EEG power spectra. Pemoline was given orally in increasing doses ranging from 20 to 80 mg/day. EEG was recorded during baseline and at three fixed intervals during the treatment. Clinical response was assessed by objective and subjective ratings. In the adult sample, the drug produced two opposite patterns of EEG response which allowed us to discriminate by the 1st day of treatment responders who reported a paradoxical calming and non-responders who reported a worsening in anxiety. Inconsistent EEG power changes produced by the drug in children did not allow the discrimination of responders and non-responders. Children did not show paradoxical signs of sedation. EEG and clinical data suggest that adults and children show different drug response and that the paradoxical sedation is present only in adults.

In the present study the interaction of zetidoline, a new antipsychotic, with the serotonergic system of the rodent brain was investigated in comparison with known neuroleptics. The pharmacological tests were L-5-hydroxytryptophan syndrome in mice and tryptamine-induced clonic seizures in rats. Biochemical tests were the in vitro binding of 3 H-zetidoline to rat brain membranes and the serotonin metabolism and turnover in vivo in the rat cerebral cortex and brainstem. The results indicate that zetidoline, unlike haloperidol and chlorpromazine, at doses higher than those active on the dopaminergic system, shows no or very weak antiserotonergic activity in behavioral tests.

Abnormal anterior pituitary responsiveness to acute administration of thyrotropin-releasing hormone was investigated in 8 patients, 6 women and 2 men, with primary affective disorders in a depressive

Bromocriptine, at the optimal dose and time of 4 mg/kg, 90 min, increased the content of acetylcholine in the rat striatum by about 30% without affecting the acetylcholine content in other brain regions. Striatal choline acetyltransferase and acetylcholinesterase activities and sodium-dependent high affinity choline uptake were not affected by the in vivo administration or the in vitro incubation with even high amounts of the drug. The increase in striatal acetylcholine by bromocriptine was mediated through the dopaminergic system since pretreatment with pimozide or penfluridol, powerful dopamine receptor antagonists, completely prevented the effect while parachlorophenylaline and phenoxybenzene pretreatment were ineffective. The action of bromocriptine, differently from that of apomorphine, was also blocked upon inhibition of tyrosine hydroxylase by alphamethylparatyrosine, suggesting that intact catecholamine synthesis is necessary for the drug to act. The requirement of dopamine by bromocriptine was further indicated when no potentiation of the cholinergic response to bromocriptine occurred following induction of dopamine receptor supersensitivity by long-term 6-hydroxydopamine lesion of the nigroneostriatal pathway. On the other hand, evidence is presented to show that bromocriptine acts in synergism with dopamine as the latency period for the onset of bromocriptine's cholinergic action was significantly decreased when it was administered in combination with a subthreshold dose of L-dopa, the dopamine precursor. There also was no summation of bromocriptine's increase with apomorphine's increase in striatal acetylcholine content at supramaximal doses possibly indicating that the same population of intrastriatal cholinergic neurons is the common target of both drugs. It is proposed that bromocriptine exerts an inhibitory effect on the striatal cholinergic neurons through a stimulation of the dopaminergic system but, differently from apomorphine, it requires the presence of endogenous dopamine for its action.

Ten chronic schizophrenic patients were given bromocriptine in doses increasing from 1.25 to 5 mg over 6 days (the low-dose therapy) and then up to 40 mg over 15 days (the high-dose therapy). Psychopathological status was assessed using the Brief Psychiatric Rating Scale, twice daily the first 6 days, and every 2 days thereafter. The prolactin (PRL) response to haloperidol stimulation (1 mg i.v.) was measured in five cases before and 3 days after the end of high-dose therapy, and in one patient before and 3 days after the end of low-dose therapy. Electroencephalographic sleep studies were carried out before therapy and every 2 nights during low-dose therapy in five patients, and in two cases during high-dose therapy. Bromocriptine therapy modified neither clinical symptomatology nor sleep patterns. The PRL response to haloperidol after therapy was markedly lower than that before therapy in the five patients treated with high doses, and markedly higher in the single patient tested who was treated only with low-dose therapy.